Maintenance of intracellular Ca2+ basal concentration in airway smooth muscle

In airway smooth muscle, the intracellular basal Ca2+ concentration [(b)(Ca2+)(i)] must be tightly regulated by several mechanisms in order to maintain a proper airway patency. The (b)[Ca2+](i) is efficiently regulated by sarcoplasmic reticulum Ca2+-ATPase 2b, plasma membrane Ca2+-ATPase 1 or 4 and by the Na+/Ca2+ exchanger. Membranal Ca2+ channels, including the L-type voltage dependent Ca2+ channel (L-VDCC), T-type voltage dependent Ca2+ channel (T-VDCC) and transient receptor potential canonical 3 (TRPC3), appear to be constitutively active under basal conditions via the action of different signaling pathways, and are responsible for Ca2+ influx to maintain (b)[Ca2+](i). The two types of voltage-dependent Ca2+ channels (L- and T-type) are modulated by phosphorylation processes mediated by mitogen-activated protein kinase kinase (MEK) and extracellular-signal-regulated kinase 1 and 2 (ERK1/2). The MEK/ERK signaling pathway can be activated by G-protein-coupled receptors through the alpha(q) subunit when the endogenous ligand (i.e., acetylcholine, histamine, leukotrienes, etc.) is present under basal conditions. It may also be stimulated when receptor tyrosine kinases are occupied by the appropriate ligand (cytokines, growth factors, etc.). ERK1/2 phosphorylates L-VDCC on Ser(496) of the beta(2) subunit and Ser(1928) of the alpha(1) subunit, decreasing or increasing the channel activity, respectively, and enabling it to switch between an open and closed state. T-VDCC is also probably phosphorylated by ERK1/2, although further research is required to identify the phosphorylation sites. TRPC3 is directly activated by diacylglycerol produced by phospholipase C (PLC beta or (gamma)). Constitutive inositol 1,4,5-trisphosphate production induces the release of Ca2+ from the sarcoplasmic reticulum through inositol triphosphate receptor 1. This ion induces Ca2+-induced Ca2+ release through the ryanodine receptor 2 (designated as Ca2+ 'sparks'). Therefore, several Ca2+ handling mechanisms are finely tuned to regulate basal intracellular Ca2+ concentrations. It is conceivable that alterations in any of these processes may render airway smooth muscle susceptible to develop hyperresponsiveness that is observed in ailments such as asthma.